EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis.
Eph receptors have been implicated in regulating a diverse array of cellular functions in the developing nervous system. Recently, Eph receptors have been shown to promote cell death in adult germinal zones; however, their mechanisms of action remain ill-defined. In this study, we demonstrate that EphA4 is a new member of the dependence receptors family, which can initiate cell death in the absence of its ligand ephrinB3. Upon removal of its ligand, EphA4 triggers cell death that is dependent on caspase activation as caspase inhibitors prevent cell death. EphA4 itself is cleaved by caspase-3-like caspase in the intracellular domain at position D773/774, which is necessary for cell death initiation as mutation of the cleavage site abolishes apoptosis. In the adult subventricular zone, abolishing ephrinB3 results in increased cell death, while the absence of EphA4 results in excessive numbers of neuroblasts. Furthermore, infusion of soluble ephrinB3 into the lateral ventricle reduced cell death, and together these results support a dependence role for EphA4 in adult neurogenesis.
Furne
Céline
C
Laboratory Apoptosis Cancer and Development, CNRS UMR 5238, Center Léon Bérard, University of Lyon, Lyon, France.
Ricard
Jerome
J
Cabrera
Jorge Ruben
JR
Pays
Laurent
L
Bethea
John R
JR
Mehlen
Patrick
P
Liebl
Daniel J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002552:Cerebral Ventricles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D036389:Ephrin-B3 / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D036122:Receptor, EphA4 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013379:Substrate Specificity / Q000187:drug effects
D036389:Ephrin-B3; D008024:Ligands; D036122:Receptor, EphA4; D053148:Caspase 3